{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T05:55:39Z","timestamp":1768456539961,"version":"3.49.0"},"reference-count":22,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2024,3,9]],"date-time":"2024-03-09T00:00:00Z","timestamp":1709942400000},"content-version":"vor","delay-in-days":68,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Richard King to Royal Free Charity"},{"name":"Medical Research Council Research Training Fellowship","award":["MR\/T001631\/1"],"award-info":[{"award-number":["MR\/T001631\/1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,3,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>Using an integrated multi-omic analysis, we previously derived a candidate marker that estimates the modified Rodnan Skin Score (mRSS) and thus the severity of skin involvement in SSc. In the present study we explore technical and biological validation of this composite marker in a well-characterized cohort of SSc patients.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Cartilage oligomeric matrix protein (COMP), collagen type IV (COL4A1), tenascin-C (TNC) and spondin-1 (SPON1) were examined in serum samples from two independent cohorts of patients with dcSSc. The BIOlogical Phenotyping of diffuse SYstemic sclerosis cohort had previously been used to derive the composite marker and Molecular Determinants to Improve Scleroderma (SSc) treatment (MODERNISE) was a novel validation cohort. Multiple regression analysis derived a formula to predict the mRSS based on serum ELISA protein concentration.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The serum concentration of two of the proteins\u2014COMP and TNC\u2014positively correlated with the mRSS, particularly in early dcSSc patients. Interpretable data could not be obtained for SPON1 due to technical limitations of the ELISA. COL4A1 showed a correlation with disease duration but not overall mRSS. Patients receiving MMF showed lower serum concentrations of COMP, COL4A1 and TNC and a lower composite biomarker score not established on treatment. A revised ELISA-based three-protein composite formula was derived for future validation studies.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Although more validation is required, our findings represent a further step towards a composite serum protein assay to assess skin severity in SSc. Future work will establish its utility as a predictive or prognostic biomarker.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/rap\/rkae039","type":"journal-article","created":{"date-parts":[[2024,3,8]],"date-time":"2024-03-08T22:53:14Z","timestamp":1709938394000},"source":"Crossref","is-referenced-by-count":2,"title":["Testing a candidate composite serum protein marker of skin severity in systemic sclerosis"],"prefix":"10.1093","volume":"8","author":[{"given":"Elen","family":"Roblin","sequence":"first","affiliation":[{"name":"Department of Rheumatology, Royal Free Hospital , London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristina E N","family":"Clark","sequence":"additional","affiliation":[{"name":"Centre for Rheumatology, University College London , London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claire","family":"Beesley","sequence":"additional","affiliation":[{"name":"Centre for Rheumatology, University College London , London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5474-0053","authenticated-orcid":false,"given":"Voon H","family":"Ong","sequence":"additional","affiliation":[{"name":"Centre for Rheumatology, University College London , London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3975-8938","authenticated-orcid":false,"given":"Christopher P","family":"Denton","sequence":"additional","affiliation":[{"name":"Centre for Rheumatology, University College London , London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2024,3,9]]},"reference":[{"key":"2024042001261188000_rkae039-B1","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1002\/art.41153","article-title":"Using autoantibodies and cutaneous subset to develop outcome-based disease classification in systemic sclerosis","volume":"72","author":"Nihtyanova","year":"2020","journal-title":"Arthritis Rheumatol"},{"key":"2024042001261188000_rkae039-B2","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1186\/s13075-019-1867-1","article-title":"Survival and prognosis factors in systemic sclerosis: data of a French multicenter cohort, systematic review, and meta-analysis of the literature","volume":"21","author":"Pokeerbux","year":"2019","journal-title":"Arthritis Res Ther"},{"key":"2024042001261188000_rkae039-B3","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1038\/s41584-022-00765-9","article-title":"Skin involvement in early diffuse cutaneous systemic sclerosis: an unmet clinical need","volume":"18","author":"Herrick","year":"2022","journal-title":"Nat Rev Rheumatol"},{"key":"2024042001261188000_rkae039-B4","doi-asserted-by":"crossref","first-page":"2445","DOI":"10.1002\/1529-0131(200011)43:11<2445::AID-ANR11>3.0.CO;2-Q","article-title":"Skin thickness score as a predictor and correlate of outcome in systemic sclerosis. High-dose versus low-dose penicillamine trial","volume":"43","author":"Clements","year":"2000","journal-title":"Arthritis Rheum"},{"key":"2024042001261188000_rkae039-B5","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1136\/ard.2009.127621","article-title":"Skin thickness progression rate: a predictor of mortality and early internal organ involvement in diffuse scleroderma","volume":"70","author":"Domsic","year":"201","journal-title":"Ann Rheum Dis"},{"key":"2024042001261188000_rkae039-B6","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1136\/annrheumdis-2018-213455","article-title":"Progressive skin fibrosis is associated with a decline in lung function and worse survival in patients with diffuse cutaneous systemic sclerosis in the European Scleroderma Trials and Research (EUSTAR) cohort","volume":"78","author":"Wu","year":"2019","journal-title":"Ann Rheum Dis"},{"key":"2024042001261188000_rkae039-B7","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s13075-020-2113-6","article-title":"Early trajectories of skin thickening are associated with severity and mortality in systemic sclerosis","volume":"22","author":"Ledoult","year":"2020","journal-title":"Arthritis Res Ther"},{"key":"2024042001261188000_rkae039-B8","doi-asserted-by":"crossref","first-page":"2422","DOI":"10.1002\/art.22721","article-title":"Relationship between change in skin score and disease outcome in diffuse cutaneous systemic sclerosis: application of a latent linear trajectory model","volume":"56","author":"Shand","year":"2007","journal-title":"Arthritis Rheum"},{"key":"2024042001261188000_rkae039-B9","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1093\/rheumatology\/kez529","article-title":"Skin improvement is a surrogate for favourable changes in other organ systems in early diffuse cutaneous systemic sclerosis","volume":"59","author":"Nevskaya","year":"2020","journal-title":"Rheumatology (Oxford)"},{"key":"2024042001261188000_rkae039-B10","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1093\/rheumatology\/kez299","article-title":"Changes in skin score in early diffuse cutaneous systemic sclerosis are associated with changes in global disease severity","volume":"59","author":"Zheng","year":"2020","journal-title":"Rheumatology (Oxford)"},{"key":"2024042001261188000_rkae039-B11","doi-asserted-by":"crossref","first-page":"11","DOI":"10.5301\/jsrd.5000231","article-title":"Standardization of the modified Rodnan skin score for use in clinical trials of systemic sclerosis","volume":"2","author":"Khanna","year":"2017","journal-title":"J Scleroderma Relat Disord"},{"key":"2024042001261188000_rkae039-B12","doi-asserted-by":"crossref","first-page":"v53","DOI":"10.1093\/rheumatology\/kex202","article-title":"Assessment of skin involvement in systemic sclerosis","volume":"56","author":"Kum\u00e1novics","year":"2017","journal-title":"Rheumatology (Oxford)"},{"key":"2024042001261188000_rkae039-B13","doi-asserted-by":"crossref","first-page":"e507","DOI":"10.1016\/S2665-9913(22)00094-7","article-title":"Integrated analysis of dermal blister fluid proteomics and genome-wide skin gene expression in systemic sclerosis: an observational study","volume":"4","author":"Clark","year":"2022","journal-title":"Lancet Rheumatol"},{"key":"2024042001261188000_rkae039-B14","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.jbspin.2011.02.022","article-title":"Cartilage Oligomeric Matrix Protein (COMP) in systemic sclerosis (SSc): role in disease severity and subclinical rheumatoid arthritis overlap","volume":"79","author":"Gheita","year":"2012","journal-title":"Joint Bone Spine"},{"key":"2024042001261188000_rkae039-B15","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.1136\/ard.2007.082099","article-title":"COMP: a candidate molecule in the pathogenesis of systemic sclerosis with a potential as a disease marker","volume":"67","author":"Hesselstrand","year":"2008","journal-title":"Ann Rheum Dis"},{"key":"2024042001261188000_rkae039-B16","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1111\/1346-8138.13564","article-title":"Possible association of elevated serum collagen type IV level with skin sclerosis in systemic sclerosis","volume":"44","author":"Motegi","year":"2017","journal-title":"J Dermatol"},{"key":"2024042001261188000_rkae039-B17","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1038\/nrrheum.2016.99","article-title":"Systemic sclerosis: tenascin C perpetuates tissue fibrosis","volume":"12","author":"Ummarino","year":"2016","journal-title":"Nat Rev Rheumatol"},{"key":"2024042001261188000_rkae039-B18","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1089\/wound.2017.0732","article-title":"Toll-like receptor-4 signaling drives persistent fibroblast activation and prevents fibrosis resolution in scleroderma","volume":"6","author":"Bhattacharyya","year":"2017","journal-title":"Adv Wound Care (New Rochelle)"},{"key":"2024042001261188000_rkae039-B19","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.jid.2016.08.027","article-title":"A proteome-derived longitudinal pharmacodynamic biomarker for diffuse systemic sclerosis skin","volume":"137","author":"Rice","year":"2017","journal-title":"J Invest Dermatol"},{"key":"2024042001261188000_rkae039-B20","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1016\/S2213-2600(20)30318-0","article-title":"Tocilizumab in systemic sclerosis: a randomised, double-blind, placebo-controlled, phase 3 trial","volume":"8","author":"Khanna","year":"2020","journal-title":"Lancet Respir Med"},{"key":"2024042001261188000_rkae039-B21","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/S2213-2600(20)30330-1","article-title":"Efficacy and safety of nintedanib in patients with systemic sclerosis-associated interstitial lung disease treated with mycophenolate: a subgroup analysis of the SENSCIS trial","volume":"9","author":"Highland","year":"2021","journal-title":"Lancet Respir Med"},{"key":"2024042001261188000_rkae039-B22","doi-asserted-by":"crossref","first-page":"1608","DOI":"10.1002\/art.42510","article-title":"Efficacy and safety of lenabasum, a cannabinoid type 2 receptor agonist, in a phase 3 randomized trial in diffuse cutaneous systemic sclerosis","volume":"75","author":"Spiera","year":"2023","journal-title":"Arthritis Rheumatol"}],"container-title":["Rheumatology Advances in Practice"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/rheumap\/advance-article-pdf\/doi\/10.1093\/rap\/rkae039\/56917434\/rkae039.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/rheumap\/article-pdf\/8\/2\/rkae039\/57287300\/rkae039.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/rheumap\/article-pdf\/8\/2\/rkae039\/57287300\/rkae039.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,20]],"date-time":"2024-04-20T01:26:43Z","timestamp":1713576403000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/rheumap\/article\/doi\/10.1093\/rap\/rkae039\/7625072"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,1]]},"references-count":22,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2024,3,14]]}},"URL":"https:\/\/doi.org\/10.1093\/rap\/rkae039","relation":{},"ISSN":["2514-1775"],"issn-type":[{"value":"2514-1775","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,1,1]]},"published":{"date-parts":[[2024,1,1]]},"article-number":"rkae039"}}